Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion

J M Locke, G da Silva Xavier, H R Dawe, G A Rutter, L W Harries

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)
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Abstract

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by progressive beta cell dysfunction, with changes in gene expression playing a crucial role in its development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and therefore alterations in miRNA levels may be involved in the deterioration of beta cell function.

METHODS: Global TaqMan arrays and individual TaqMan assays were used to measure islet miRNA expression in discovery (n = 20) and replication (n = 20) cohorts from individuals with and without type 2 diabetes. The role of specific dysregulated miRNAs in regulating insulin secretion, content and apoptosis was subsequently investigated in primary rat islets and INS-1 cells. Identification of miRNA targets was assessed using luciferase assays and by measuring mRNA levels.

RESULTS: In the discovery and replication cohorts miR-187 expression was found to be significantly increased in islets from individuals with type 2 diabetes compared with matched controls. An inverse correlation between miR-187 levels and glucose-stimulated insulin secretion (GSIS) was observed in islets from normoglycaemic donors. This correlation paralleled findings in primary rat islets and INS-1 cells where overexpression of miR-187 markedly decreased GSIS without affecting insulin content or apoptotic index. Finally, the gene encoding homeodomain-interacting protein kinase-3 (HIPK3), a known regulator of insulin secretion, was identified as a direct target of miR-187 and displayed reduced expression in islets from individuals with type 2 diabetes.

CONCLUSIONS/INTERPRETATION: Our findings suggest a role for miR-187 in the blunting of insulin secretion, potentially involving regulation of HIPK3, which occurs during the pathogenesis of type 2 diabetes.

Original languageEnglish
Pages (from-to)122-128
Number of pages7
JournalDiabetologia
Volume57
Early online date23 Oct 2013
DOIs
Publication statusPublished - Jan 2014

Keywords

  • Adult
  • Aged
  • Animals
  • Cell Line
  • Cells, Cultured
  • Diabetes Mellitus, Type 2/metabolism
  • Glucose/pharmacology
  • Humans
  • Insulin/secretion
  • Insulin-Secreting Cells/drug effects
  • Intracellular Signaling Peptides and Proteins/genetics
  • MicroRNAs/genetics
  • Middle Aged
  • Protein-Serine-Threonine Kinases/genetics
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Glucose-stimulated insulin secretion
  • HIPK3
  • Islets
  • MicroRNA
  • Type 2 diabetes

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